1. Field of the Invention
The present disclosure generally relates to antibodies specific for ICAM-1 and compositions comprising the same and methods for treating related disease using the same.
2. Description of the Related Art
Tolerance to specific antigens is the ultimate therapeutic goal in two major immunological fields, autoimmunity and transplantation rejection. Over the past several decades, the generation of a large array of immunosuppressive agents has increased the number of therapeutic tools available to address these two issues. The focus has now shifted to tackling the side effects of long-term immunosuppression. The final goal is to achieve T and B cell tolerance that is antigen specific without the need for long-term generalized immunosuppression.
According to the mechanisms underlying peripheral T cell tolerance upto now, DCs (Dendritic Cells) have a key role in immune regulation (Steinman et al., 2003. Annu. Rev. Immunol. 21:685-711) and antigen presentation by immature and semimature DCs results in immune tolerance rather than effective T cell immunity because of the failure to provide sufficient co-stimulatory signals (Reis e Sousa, 2006. Nat. Rev. Immunol. 6: 476-483). These tolerogenic DCs are characterized by low-level expression of surface MHC molecules and several other co-stimulatory receptors and the production of low levels of Th1 cytokines, notably IL-12p70 (Morelli and Thomson, 2007. Nat. Rev. Immunol. 7: 610-621).
ICAM-1 is a cell surface glycoprotein and a member of the immunoglobulin superfamily composed of five extracellular immunoglobulin-like domains) and expresses at low level in various types of cells but the expression is greatly increased in the inflammatory region. ICAM-1 binds to LFA-1 (Leukocyte Function Associated Antigen-1) expressed on the surface of T cells, and functions as a costimulatory factor for antigen presenting cells thus medicating the interaction between antigen presenting cells such as DC and T cells (Transplantation. 1999, 67:729-736). Also the expression of ICAM-1 is increased at the inflammatory site of endothelial cells of blood vessels and is involved in the migration of leukocytes to the inflammatory site.
Thus several antibodies to ICAM-1 have been developed to regulate the inflammatory and immunological response. Among them is an IgG2a mAb R6.5 (BIRR-1, Enlimomab). It has been found that it inhibits the adhesion of leukocytes to endothelial cells of the blood vessel thus reducing the extravasation of leukocytes into tissue and the damages to the inflammatory tissues (J Immunol. 1990, 144: 4604-4612). However, Enlimomab has been found to have side effects such as fever and leukocytopenia and not to able to reduce the rate of acute rejection or the risk of delayed onset of graft function after renal transplantation in a randomized multicenter study (Transplantation 1999, 67:729-736).
European patent application 0 459 577 discloses an antibody to ICAM-1 inhibiting the adhesion of rhinovirus to cellular receptors. U.S. Pat. No. 7,696,324 discloses a humanized antibody of what is disclosed in EP 0 459 577.
ICAM-1 plays a key role in the defense to bacterial infection by host cells since its role in the migration of leukocytes through endothelial cells in the initiation of immunological response. Therefore there are needs to develop antibodies based on the immunological regulation via the interaction between T cells and antigen presenting cells without affecting the migration of leukocytes through endothelial cells of the blood vessel.